Chronic rhinosinusitis (CRS) is a prevalent inflammatory disease with major public health impact. Genetic and environmental factors contribute to risk, but interactions between them are poorly understood. In this application, we propose to a systems genetics approach to discover genes and pathways involved in epithelial response to two important pathogens involved in CRS: human rhinovirus (HRV), which shows clinical and epidemiologic association with CRS, and Staphylococcus aureus (SA), which has been implicated in CRS-related epithelial inflammation. In this application, we propose the hypothesis that epithelial respose to HRV and SA trigger a cascade of events that result in chronic sinus inflammation, and that inter-individual differences in response to these pathogens are associated with disease susceptibility and severity. To test this hypothesis, we will examine changes in global gene expression (RNA) and methylation patterns in primary cultured sinonasal epithelial cells treated with HRV, SA, or vehicle (control) and perform expression quantitative trait locus (eQTL) and methylation quantitative trait locus (meQTL) mapping of transcript levels and methylation patterns, respectively, to identify functional SNPs (eQTL, meQTL) underlying variation in response to these stimuli, and differences between CRS and non-CRS subjects. Functional SNPs will be taken fonrt/ard for association studies in a large cohort of ethnically diverse, well-characterized subjects with sinus disease to identify risk alleles, modifiers of disease course, and modifiers of response to environmental exposures. We will employ state-of-the-art genomic and bioinformative tools and harness the benefits ofthe Chronic Rhinosinusitis Integrative Program (CRISP) project that includes broad expertise in epidemiology, genetics, molecular and cellular biology, and clinical studies to discover and characterize the genetic architecture of CRS. Evaluating the molecular responses to these key pathogens would constitute a major contribution toward better understanding of CRS and provide a paradigm for elucidating genetic and environmental risk factors for this disorder and other common, complex diseases ofthe upper airway.